The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a target-oriented treatment of pain conditions which is right for the patient, which is to be understood as the successful and satisfactory treatment of pain for the patients, is documented in the large number of scientific works which have recently and over the years appeared in the field of applied analgesics or on basic research on nociception.
The facilitated, carrier-mediated transport of nucleosides across mammalian cell
membranes can be inhibited by a number of ligands including nucleoside derivatives such as nitrobenzylthioinosine (NBTI, 1) (Plagemann, P. G. W.; Wohlhueter, R. M.; Woffendin, C. Biochim Biophys Acta 1988, 947, 405-443), and non-nucleoside compounds including marketed substances such as dipyridamole and dilazep. (Thom, J. A.; Jarvis, S. M. Gen. Pharmac. 1996, 27, 613-620; I Jzerman, A. P.; Voorschuur, A. H. Naunyn-Schmiedeberg's Arch Pharmacol 1990, 342, 336-341 (and refs therein)). Such compounds contribute to the physiological actions of adenosine. Through their blockade of the transport protein they increase the extracellular concentration of adenosine. This increase in adenosine levels causes a more profound occupancy of adenosine receptors through which adenosine exerts many of its physiological effects. The high hydrophilicity of NBTI and other transport inhibitors, however, may hinder their penetration into the CNS, where adenosine is involved in e.g., counteracting neuropathic pain.
An earlier study indicated that a nitro group preferably at the 4-position of the benzyl moiety in NBTI is a prime factor in determining the potency of inhibition of nucleoside transport in human erythrocytes. (Paul, B.; Chen, M. F.; Paterson, A. R. P. J. Med. Chem. 1975, 18, 968-973; Baldwin, S. A.; Mackey, J. R.; Cass, C. E.; Young, J. D. Molecular Medicine Today 1999, 5, 216-224). To gain further information on the interaction of NBTI with the nucleoside transporter-associated binding site we systematically replaced a number of substituents at C6 and N9. Also the 1-deaza-2-chloro analog of NBTI was prepared. A primary aim was to provide substances with reduced polarity while maintaining substantial affinity for the transport protein.